US3851044A - Bone seeking technetium 99m stannous phosphate complex - Google Patents

Bone seeking technetium 99m stannous phosphate complex Download PDF

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Publication number
US3851044A
US3851044A US00288577A US28857772A US3851044A US 3851044 A US3851044 A US 3851044A US 00288577 A US00288577 A US 00288577A US 28857772 A US28857772 A US 28857772A US 3851044 A US3851044 A US 3851044A
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phosphate
pyrophosphate
bone
complex
stannous
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N Adler
L Camin
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Bristol Myers Squibb Pharma Co
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New England Nuclear Corp
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Application filed by New England Nuclear Corp filed Critical New England Nuclear Corp
Priority to US00288577A priority Critical patent/US3851044A/en
Priority to CA000179088A priority patent/CA1120687A/en
Priority to DE19732344802D priority patent/DE2344802A1/de
Priority to DE2344802A priority patent/DE2344802C2/de
Priority to DE2366614A priority patent/DE2366614C2/de
Priority to GB2236375A priority patent/GB1441146A/en
Priority to GB4268673A priority patent/GB1441145A/en
Priority to US05/410,086 priority patent/US4016249A/en
Publication of US3851044A publication Critical patent/US3851044A/en
Application granted granted Critical
Priority to US05/657,923 priority patent/US4082840A/en
Priority to CA278,675A priority patent/CA1080432A/en
Assigned to E.I. DU PONT DE NEMOURS AND COMPANY, INCORPORATED reassignment E.I. DU PONT DE NEMOURS AND COMPANY, INCORPORATED ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: NEW ENGLAND NUCLEAR CORPORATION
Assigned to DU PONT MERCK PHARMACEUTICAL COMPANY reassignment DU PONT MERCK PHARMACEUTICAL COMPANY ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: E.I. DU PONT DE NEMOURS AND COMPANY
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • Tc technetium- 99m
  • the bone uptake (the percent of the total dosage which becomes concentrated in the skeletal structure within a certain time after in vivo intravenous administration) of such Tccontaining complex and the ratios of such bone uptake to uptake of the Tc by the other organs of the body (the higher these ratios the better), i.e. radioactive contrast, are not nearly as high as with radioactive strontium.
  • the phosphate moiety of the Tc-stannous-phosphate complex which has been suggested in the aforesaid Radiology publication, comprises pyrophosphate (P O (which is a linear polyphosphate moiety of molecular weight less than 300), the bone uptake, bone/blood ratio, bone/liver ratio, bone/ G.I. ratio and bone/kidneys ratio are substantially increased.
  • P O pyrophosphate
  • Such phosphate moiety contains no more than about 15 to 20 or 25%, preferably no more than 5 to 10% and more preferably no more than 5% (less than 5% is the most preferred), by weight of linear or branched chain polyphosphate (formula P O of molecular weight greater than that of pyrophosphate.
  • Tc-Sn++-pyrophosphate complex is administered to the mammal in relatively small dosages of substantially less than 20 or 25, preferably substantially less than 8 or 10 and still more preferably less than 5 or 6 (between 0.01 or 0.10 and 3 and even less provide excellent results), milligrams pyrophosphate moiety per kilogram of body weight of the mammal.
  • phosphate moiety refers to the phosphorus and oxygen atoms only of the phosphate.
  • polyphosphates of formula P 0 (n+2) and molecular weight greater than that of pyrophosphate seems to reduce bone take-up and the aforesaid ratios, as compared to complexes without such higher molecular weight polyphosphate.
  • some of such higher molecular weight polyphosphates can be tolerated, preferably not more than about 15 to 20% or 25%, more preferably no more than 5% to 10% and still more preferably not more than 5% (less than 5% is the most preferred), by weight of the total phosphate moiety.
  • the rest of the phosphate moiety is preferably a ring phosphate of formula P O (with n preferably being 3 which is trimetaphosphate) and/ or ortho phosphate, and preferably a ring phosphate only, although the aforesaid limited amounts of higher molecular weight linear polyphosphates can be tolerated.
  • the complex is made from a water soluble alkali metal (preferably sodium) or ammonium salt or acid salt of the pyrophosphate, e.g. sodium pyrophosphate.
  • a water soluble alkali metal preferably sodium
  • ammonium salt or acid salt of the pyrophosphate e.g. sodium pyrophosphate.
  • the sodium pyrophosphate is admixed with a stannous salt, e.g. SnCl (the stannous salts of other acids which are pharmaceutically acceptable, i.e. safely intravenously administered, can be used) to form the stannous-pyrophosphate complex, the pH of which is adjusted to 3-8, preferably -8, by a pharmaceutically acceptable acid, such as HCl, or base, such as NaOH or Na CO or NaHCO followed by admixing with the stannous-pyrophosphate complex, an aqueous saline solution of radioactive sodium pertechnetate Tc) to form the Tc-stannous-pyrophosphate complex at the time it is desired to intravenously administer the Tc complex.
  • a stannous salt e.g. SnCl (the stannous salts of other acids which are pharmaceutically acceptable, i.e. safely intravenously administered, can be used
  • a pharmaceutically acceptable acid such as HCl, or base, such as NaOH
  • the stannous-pyrophosphate complex may be sealed in a sterile non-pyrogenic container or vial as a solution or a lyophilized solid and shipped as a kit with the freshly generated sterile and non-pyrogenic Tc being added aseptically at the situs just prior to use.
  • a fifth acetone fraction of the EMU Glass H (oonta g the next higher molecular weight polyphosphates) (composition given in Table 2) is precipitated out of the remaining supernatant solution of 1-4, as an oil, by adding more acetone.
  • a seventh acetone fraction of FMC Glass H (composition given in Table 2) is precipitated out of the remaining supernatant solution of 1-6, as a solid precipitate of the next higher molecular weight polyphosphates by adding more acetone.
  • Sodium tripolyphosphate 10 Sodium tetrapolyphosphate-NanP4013-a polyphosphate-phosphate moiety having a MW. of 348. It, together with the pyrophosphate and tripolyphosphate, fall in the class of linear chain polyphosphates having the general formula PHOsni-F -An aqueous solution of each of the phosphate composition samples 1 through 1 0 (40 mg. phosphate/1 ml. solution) were made with distilled water in which the dissolved oxygen content was reduced in a conventional manner by bubbling through such water gaseous nitrogen for a period of two hours. The water and phosphates were mixed to form the solutions in a nitrogen atmosphere and in a nitrogen flushed container.
  • aqueous solution 3N sodium hydroxide (sodium carbonate or bicarbonate can also be used), in the case of samples 1 through 7 and 9 and 10, and 3N HCl, in the case of sample 8, is then added to each sample to give a pH of 5.0 to achieve a pH suitable for subsequent intravenous in vivo administration into the body of a mammal, in this case adult mice.
  • the pH adjustment is preferably done under a nitrogen atmosphere also.
  • the solutions are sterilized by passing them through a Millipore biological filter of 0.22 micron pore size under a nitrogen atmosphere. Thereafter milliliter portions of each of the sterile solutions are poured into individual sterile and non-pyrogenic storage glass vials under a nitrogen atmosphere.
  • vials are lyophilized by conventional freeze drying equipment under aseptic conditions to remove water. This provides a solid stannousphosphate complex which aids in shipping and storage and which is more stable than the complex in solution.
  • Each vial contains 1.35 mg. SnCl and 40 mg. of the phosphate.
  • the vials can be sealed and stored until needed subsequently to form the technetium 99m stannous-phosphate complex at the use situs.
  • sample 11 An eleventh sample was prepared in the manner set forth above by diluting sample 8 to a concentration of 1 mg. of phosphate per ml. of solution. This was labeled sample 11.
  • Each of the technetium-99m-stannous-phosphate com refers to the phosphate moiety of sodium trimetaphosphate
  • Tetrameta R refers to the phosphate moiety of sodium tetrametaphosphate, both trimeta and tetrametaphosphates falling within the class of cyclic or ring phosphates having the formula P O in which Pentapoly plex-contammg solutlons 1s aseptically 1ntravenously 1nand Longer Llnear Cha1ns refers to the phosphate moiected 1n VlVO 1nto a ve1n 1n the tail of adult mice (average ety of sodium pentapolyphosphate and longer linear (linwelght 0.040 kgs.) 1n an amount equal to between 1 and car as used herein includes straight and branched linear 3 mC1 and a volume of (M2 ml.
  • sample 8 (8 mg. of phosphate per phosphate chains) polyphosphates of formula ml. solutlon in samples 1 through and 1 mg. phosphate 10 P O per ml. solution in sample 11). Also sample 8 was inn jected in the same manner except that a volume of 0.015 in which Average M.W. refers to the average molecular ml. was injected instead of 0.12 ml. to reduce the dosage weight of the phosphate moiety of the sample and in of the complex by a factor of 8. This was labeled sample which Fraction in Raw Stock with reference to sam- 12.
  • ples 1-1, 12, 13, 14, 1-6, l-7 and l-8 refer to the Three hours after intravenous administration, some of normalized percent by weight of each of these samples the mice to which each sample was administered were in sample 1, whlch is the raw stock which is fractionated.
  • Phosphate sample 1 (FMC) 1-1 1-2 1-3 1-4 1-6 1-7 1-8 2 4 5 6 7 8 9 10 11 12 5 4 4 4 5 5 1s 29 17 30 58 32 2 34 13 5 35 24 0.5 7 6 7 8 3 29 19 24 32 78 38 2 5 20 3 47 36 5 6 8 7 11 11 37 63 36 55 140 55 17 49 31 11 81 32 Bone/kidneys 1 1 1 1 3 2 9 12 8 9 13 12 3 9 5 1 12 6 Percent having phosphate moiety M.W. less than 300 15 3 3 5 13 17 90 100 55 99 98 98 100 100 100 10 100 100 Phosphate composition:
  • the uptakes (the bone uptake figures represent the average bone uptake for the skeletal system) are in terms of percent of the total technetium-99m activity injected (corrected for radioactive decay) which has collected in the various organs indicated three hours after in vivo intravenous injection, in which the ratio amounts are computed from the uptake amounts adjusted to compen sate for the different weights of the organs and the different weights of the animals by dividing each uptake amount by the ratio expressed in percentage of the weight of such organ to the weight of the animal, in which Percent Having Phosphate Moiety M.W.
  • phosphate moiety as used herein is limited to that part of the compound or complex made up of phosphate phosphorus and oxygen atoms
  • Ortho P refers to the phosphate moiety of sodium orthophosphate
  • Pyro P refers to the phosphate moiety of sodium pyrophosphate
  • Tripoly P refers to the phosphate moiety of sodium tripolyphosphate
  • Tetrapoly P refers to the phosphate moiety of sodium tetrapolyphosphate
  • Trimeta R conventional scanning by radioactive imaging using a gamma ray-excited scintillation or gamma camera and a dual crystal rectilinear scanner was used in vivo. In vivo sci
  • the Tc-Sn++ pyrophosphate complexes of the present invention are rapidly cleared from the blood by deposition in bone and excretion into urine.
  • the technetium-99m-stannouspyrophosphate complexes are metabolizable.
  • the deposition of the -Tc-stannous-pyrophosphate complexes of the invention appears to be primarily a function of the bone blood flow as well as being related to the efficiency of the bone in extracting the complex from the blood which perfuses the bones.
  • Radiopharmaceutical Localized areas of abnormal accumulation of the radiopharmaceutical may be seen in primary malignancies of the bone, metastatic malignancies of the bone, acute or chronic osteomyelitis, arthritides, recent fractures, areas of ectopic calcification, Pagets disease, regional migratory osteoporosis, areas of aseptic necrosis and in general any pathological situation involving bone in which there is increased osteogenic activity or localized increased osseous blood perfusion.
  • mice The acute toxicity level in mice (LD for sample No. 2 has been determined to be 150 mg./kg. body weight and for sample 6 it is 800 mg./kg. and for sample 8 it is 70 mg./kg. Subacute toxicity studies in mice of sample 2 have shown no signs of toxicity after 15 daily injections at dose levels as high as 63 mg./kg. body weight/ day. A similar subacute study in dogs indicates no signs of toxicity at a dose level of 3.6 mg./kg. body weight/ day.
  • samples 4 and 6 were only one fourth as toxic to mice as sample 2 and one-eighth as toxic to mice as sample 1.
  • the complexes of the invention have been used successfully as a skeletal imaging or scanning agent to visualize areas of altered blood flow to the bone and altered osteogenic activity, including suspected bone lesions not shown on X-ray, bone survey performed as par-t of a work-up in patients with known or suspected malignancy, to follow the response of metastatic or primary bone lesions to radiation therapy, metabolic bone disease, to diagnose arthritis and osteomyelitis, and to diag nose and determine healing rate of bone fractures.
  • the technetium-99m Tc labelling reactions involved in preparing the Tc-stannous-phosphate complexes of the invention depend on maintaining the tin in the reduced or stannous (Snstate. Oxidants present in the pertechnetate supply may adversely affect quality.
  • the radioactive dosage of the Te complex of the invention may vary from 1 to 25 mCi (millicuries) but preferably is from to mCi.
  • the dosage should preferably be substantially less than or 25, preferably less than 8 or 10 and more preferably less than 5 or 6 mg. of pyrophosphate moiety per kilogram of body weight of the mammal since greater pyrophosphate dosages than this reduces the bone-liver ratio too much. Note for example the low bone-liver ratio in sample 8 where the dosage was mg. pyrophosphate per kg. body weight compared to the bone-liver ratio of sample 11 where the dosage was 3.1 mg./kg. body weight.
  • the dosage of pyrophosphate can be kept small either by use of more dilute dosage solutions of the pure pyrophosphate, as in sample 11 or by administering smaller doses of a more concentrated complex solution, the phosphate moiety of which contains a high concentration of pyrophosphate or by more concentrated solutions of phosphate containing, in addition to the pyrophosphate, ring phosphate and/or orthophosphate which effectively dilute the pyrophosphate concentration of the dose.
  • Tc-Sn++-phosphate solution containing between 0.1 and 40, more preferably between 0.5 and 4 or 5 mgs. of pyrophosphate moiety per ml. of solution.
  • An advantage of a complex containing a relatively large amount of ring phosphate and a smaller amount of pyrophosphate is that the ring phosphate in addition to providing excellent bone up-take and bone-to-other-organ ratios is less toxic than pyrophosphate, although pyrophosphate, alone, is still not unduly toxic.
  • Scanning may be commenced as early as one hour after intravenous administration and may be as long after injection as clinically useful amounts of Tc remain in the organ.
  • Another manner of making the complex of the invention is to weigh 4 mg. of SnCl .2H O and 100 mg. of sodium pyrophosphate into a flask (the flask is sterile and non-pyrogenic and is flushed with nitrogen before weighing and is kept under nitrogen during this step and for the next step).
  • the sterile stannous chloride can first be aseptically mixed with the sterile Tc saline solution to form a Tc-stannous complex, followed by adding the sterile sodium pyrophosphate under aseptic conditions to form the Tc-stannous-pyrophosphate, adjusting the pH to 3-8, followed by intravenous injection.
  • Tc-stannousphosphate complex in which the phosphate moiety comprises pyrophosphate and in which such moiety contains no more than 25% by weight of linear polyphosphate of molecular weight greater than that of pyrophosphate (samples l-7, l-8, 2, 4, 5 and 6, 8, l1 and 12) gives surprising higher bone uptake and ratio of bone uptake to other organs, as compared to orthophosphate and other polyphosphates, e.g. tripolyphosphate, tetrapolyphosphate and longer chain polyphosphates (see samples 1, 1-2 to 1-6, 7, 9' and 10).
  • the pyrophosphate moiety of the Tc-stannous-phosphate complex may be from 1 or 2% or even less up to 100% by weight of the total phosphate moiety.
  • the pyrophosphate moiety consists of 5 or 10% or more of the total phosphate moiety, more preferably 50% or 60% or more and most preferably between and
  • the stannous (Sn++) ion is by far preferred, the divalent ferrous (Fe++) ion in the form of ferrous ascorbate, and reduced zirconium can also be used but without as good results. All these metals can exist in a plurality of redox states.
  • the phosphate may be added' to the solid SnCl as an aqueous solution, or it may be added to a solution of the SnCl to form the Sn++-phosphate complex followed by adding the Tc solution.
  • the Weight ratio of Sn++ ion to the pyrophosphate moiety may vary over a wide range, i.e. from 10- to 0.50, preferably 0.01 to 0.4. It is preferred that the molecular ratio of Sn++ to pyrophosphate moiety not exceed 2/ 1. The maximum ratio is dictated by the amount beyond which the precipitation of Sn' occurs. The minimum amount required is that amount necessary to bind a sufficient amount of Tc to the pyrophosphate to achieve good bone uptake and contrast. This can be determined by routine experiment.
  • the pH of the stannous-phosphate complex may be between 3 and 8.
  • the water used for making the complexes of the invention is distilled and is at an elevated temperature of 200 F. during removal of dissolved oxygen and reduction of oxidants by bubbling the nitrogen gas therethrough.
  • the maximum amount of Tc is that beyond the capacity of the Sn++-pyrophosphate complex to bind the Tc. This can be determined by routine thin layer radiochro-matography to determine the percent of free or unbound Tc in the complex. The minimum amount is diqated by that amount below which there is an insufficient amount to give good scanning of bone uptake and contrast, which also can be determined by routine experiment.
  • the amount of Tc added to the Sn++ pyrophosphate complex should be sufficient to achieve the counting rate desired by the doctor or laboratory personnel for the volume to be injected; ordinarily, as aforesaid, the activity dosage varies from 5 to 25 millicuries.
  • sodium pyrophosphates are preferred, any alkali metal, such as potassium and lithium, or ammonium can be used as the cation so long as it is pharmaceutically acceptable so that it can be safely administered intravenously. Also the acid pyrophosphates of such cations can be used.
  • saline water was used as the vehicle, any other vehicle which is pharmaceutically acceptable for intravenous administration can be used.
  • a metabolizable radioactive bone seeking composition for in vivo concentrating Tc in the skeletal structure of mammals comprising a technetium-99m-stannousphosphate complex, the phosphate moiety of which comprises pyrophosphate, said phosphate moiety containing no more than 25% by weight of linear polyphosphate of formulation P having a molecular weight greater than pyrophosphate.
  • composition according to claim 1 substantially 100% by weight of said phosphate moiety being said pyrophosphate.
  • a metabolizable, radioactive bone seeking composition according to claim 1 at least the major portion of 10 any phosphate in said phosphate moiety other than pyrophosphate being selected from the group consisting of orthophosphate and ring phosphate of formula P O f and combinations thereof.
  • composition according to claim 5 where the n of said P O is equal to 3.
  • composition according to claim 1 at least 5% by weight of said phosphate moiety being said pyrophosphate.
  • composition according to claim 1 said phosphate moiety comprising a mixture of said pyrophosphate, an orthophosphate and a ring phosphate of formula P O 9.
  • n is 3.
  • composition according to claim 1 wherein at least about of said phosphate moiety is said pyrophosphate.
  • a composition according to claim 1 substantially any phosphate in said phosphate moiety other than pyrophosphate being selected from the group consisting of a ring phosphate of formula P O one or more phosphates of formula (P O of which not more than 10% by weight has an n value greater than 2 and combinations thereof.
  • composition according to claim 11 wherein not more than 5% by weight of said (P O has an n value greater than 2.

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US00288577A 1972-09-13 1972-09-13 Bone seeking technetium 99m stannous phosphate complex Expired - Lifetime US3851044A (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
US00288577A US3851044A (en) 1972-09-13 1972-09-13 Bone seeking technetium 99m stannous phosphate complex
CA000179088A CA1120687A (en) 1972-09-13 1973-08-17 Bone seeking technetium 99m complex
DE19732344802D DE2344802A1 (de) 1972-09-13 1973-09-05 Technetium-99m-komplex und dessen verwendung zur radioaktiven untersuchung der skelettstruktur von saeugetieren
DE2344802A DE2344802C2 (enrdf_load_stackoverflow) 1972-09-13 1973-09-05
DE2366614A DE2366614C2 (enrdf_load_stackoverflow) 1972-09-13 1973-09-05
GB4268673A GB1441145A (en) 1972-09-13 1973-09-11 Bone seeking technetium 99m complex
GB2236375A GB1441146A (en) 1972-09-13 1973-09-11 Precursor for preparing a bone-seeking technetium-99m complex
US05/410,086 US4016249A (en) 1972-09-13 1973-10-26 Bone seeking technetium 99m complex
US05/657,923 US4082840A (en) 1972-09-13 1976-02-13 Bone seeking technetium 99m complex
CA278,675A CA1080432A (en) 1972-09-13 1977-05-18 Stannous-pyrophosphate complex

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US00288577A US3851044A (en) 1972-09-13 1972-09-13 Bone seeking technetium 99m stannous phosphate complex

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CA (1) CA1120687A (enrdf_load_stackoverflow)
DE (3) DE2344802A1 (enrdf_load_stackoverflow)
GB (2) GB1441145A (enrdf_load_stackoverflow)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3976762A (en) * 1974-07-05 1976-08-24 Minnesota Mining And Manufacturing Company Multi-organ technetium complexes production and use thereof
US4075314A (en) * 1976-04-29 1978-02-21 Mallinckrodt, Inc. Stannous pyrophosphate technetium-99m compositions
US4104366A (en) * 1975-09-29 1978-08-01 Henkel Kommanditgesellschaft Auf Aktien Compositions for preparation of aqueous solutions of low valence 99 technitium salts
US4133872A (en) * 1975-09-29 1979-01-09 Henkel Kommanditgesellschaft Auf Aktien (Henkel Kgaa) Compositions for preparation of aqueous solutions of salts of lower valence 99 technetium
US4508704A (en) * 1984-02-27 1985-04-02 The Dow Chemical Company Radioactive metals complexed with phosphonate derivatives of bicycloheptane bis(alkylamines)
US4515767A (en) * 1983-06-20 1985-05-07 The Dow Chemical Company Radioactive metals complexed with phosphonate derivatives of dicyclopentadienebis(methylamine)
US4560548A (en) * 1984-04-10 1985-12-24 The Dow Chemical Company Bone seeking Tc-99m complexes of phosphonate derivatives of bis(aminoalkyl)piperazine
US4606907A (en) * 1984-07-02 1986-08-19 The Dow Chemical Company Bone seeking Tc-99m complexes of phosphonate derivatives of polyamidoamines
US4898724A (en) * 1984-06-04 1990-02-06 The Dow Chemical Company Organis amine phosphonic acid complexes for the treatment of calcific tumors
US4910012A (en) * 1988-03-30 1990-03-20 Hoechst Aktiengesellschaft Products containing Tc-99-m-ωalkylphosphinico-1-hydroxyalkane-1,1-diphosphonates for bone scintigraphy and a process for the preparation of these products
US5066478A (en) * 1984-06-04 1991-11-19 The Dow Chemical Company Radio labeled organic amine phosphonic acid complexes for the treatment of calcific tumors
US8865123B1 (en) * 2010-09-16 2014-10-21 Mo-Sci Corporation Strontium phosphate microparticle for radiological imaging and therapy
US9849200B2 (en) 2010-09-16 2017-12-26 Mo-Sci Corporation Strontium phosphate microparticle for radiological imaging and therapy

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2281134A1 (fr) * 1974-08-06 1976-03-05 Commissariat Energie Atomique Procede de marquage au 99m technetium

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2187314B1 (enrdf_load_stackoverflow) * 1972-06-06 1975-06-20 Commissariat Energie Atomique

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3976762A (en) * 1974-07-05 1976-08-24 Minnesota Mining And Manufacturing Company Multi-organ technetium complexes production and use thereof
US4104366A (en) * 1975-09-29 1978-08-01 Henkel Kommanditgesellschaft Auf Aktien Compositions for preparation of aqueous solutions of low valence 99 technitium salts
US4133872A (en) * 1975-09-29 1979-01-09 Henkel Kommanditgesellschaft Auf Aktien (Henkel Kgaa) Compositions for preparation of aqueous solutions of salts of lower valence 99 technetium
US4075314A (en) * 1976-04-29 1978-02-21 Mallinckrodt, Inc. Stannous pyrophosphate technetium-99m compositions
US4515767A (en) * 1983-06-20 1985-05-07 The Dow Chemical Company Radioactive metals complexed with phosphonate derivatives of dicyclopentadienebis(methylamine)
US4508704A (en) * 1984-02-27 1985-04-02 The Dow Chemical Company Radioactive metals complexed with phosphonate derivatives of bicycloheptane bis(alkylamines)
US4560548A (en) * 1984-04-10 1985-12-24 The Dow Chemical Company Bone seeking Tc-99m complexes of phosphonate derivatives of bis(aminoalkyl)piperazine
US4898724A (en) * 1984-06-04 1990-02-06 The Dow Chemical Company Organis amine phosphonic acid complexes for the treatment of calcific tumors
US5066478A (en) * 1984-06-04 1991-11-19 The Dow Chemical Company Radio labeled organic amine phosphonic acid complexes for the treatment of calcific tumors
US5300279A (en) * 1984-06-04 1994-04-05 The Dow Chemical Company Organic amine phosphonic acid complexes for the treatment of calcific tumors
US4606907A (en) * 1984-07-02 1986-08-19 The Dow Chemical Company Bone seeking Tc-99m complexes of phosphonate derivatives of polyamidoamines
US4910012A (en) * 1988-03-30 1990-03-20 Hoechst Aktiengesellschaft Products containing Tc-99-m-ωalkylphosphinico-1-hydroxyalkane-1,1-diphosphonates for bone scintigraphy and a process for the preparation of these products
US8865123B1 (en) * 2010-09-16 2014-10-21 Mo-Sci Corporation Strontium phosphate microparticle for radiological imaging and therapy
US9409776B2 (en) 2010-09-16 2016-08-09 Mo-Sci Corporation Strontium phosphate microparticle for radiological imaging and therapy
US9849200B2 (en) 2010-09-16 2017-12-26 Mo-Sci Corporation Strontium phosphate microparticle for radiological imaging and therapy

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GB1441146A (en) 1976-06-30
GB1441145A (en) 1976-06-30
CA1120687A (en) 1982-03-30
DE2344802C2 (enrdf_load_stackoverflow) 1989-10-05
DE2366614C2 (enrdf_load_stackoverflow) 1989-07-06
DE2344802A1 (de) 1974-03-21

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